This invention relates to hormone receptors and, more particularly, to methods of altering the activity of estrogen receptors.
Throughout this application various publications are referenced by superscript numbers. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Gene regulatory proteins are essential for cell regulation. A well studied family of gene regulatory proteins is the large steroid hormone receptor family. These receptor proteins enable cells to respond to various lipid-soluble hormones by activating or repressing specific genes. They possess a central DNA-binding domain of about 100 amino acids. For some members of this family, a transcription-activating domain has been located in an amino-terminal region. In addition, these receptors all contain a specific hormone-binding domain in the carboxylterminal part of the protein. One member of this family is the estrogen receptor (ER). Like the other members of the steroid-hormone receptor family, estrogen receptors are activated by the binding of a small signaling molecule to a separate ligand-binding domain.
The conventional model for steroid hormone action has assumed that steroid hormone receptors act as transcriptional regulators only when complexed with their ligands. It has, however, become evident that most types of steroid receptors are present in the cell nucleus even in the absence of ligand.sup.1-3. At present, the only exception to this appears to be the glucocorticoid receptor.sup.1,4. The presence of the receptors in the nucleus, even in the absence of hormone, suggest possible additional regulatory functions for the unliganded state. We have recently found that other members of the nuclear receptor family, the thyroid hormone receptors (TR), have a dual regulatory role: in the presence of hormone they function as transcriptional activators whereas in the absence of hormone they are response element specific transcriptional repressors.sup.5. The estrogen receptor is structurally related to the TR.sup.6-8 and can also activate thyroid hormone responsive elements (TRE).
Despite these similarities, it has long been established that the estrogen receptor acts in the conventional model for steroid hormone action by acting as transcriptional regulators only when complexed to estrogen. The present invention provides, contrary to this universally believed principle, that ER does not require estrogen to act as a transcriptional regulator. Therefore, the invention provides the surprising discovery that estrogen receptor has a constitutive activator and a repressor activity in the absence of estrogen. Also provided is the discovery that mutant estrogen receptors lack this constitutive activator and the repressor activity in the absence of estrogen. Since many pathologies, for example breast cancer, are associated with estrogen, the invention satisfies a long felt need by providing methods of controlling these pathologies and screening ligands which are useful in treating the pathologies.